This invention relates to pharmaceutically acceptable amide-imide derivatives of low molecular weight homopolymers of itaconic anhydride having antitumor activity.
Itaconic acid and itaconic anhydride homopolymers and copolymers with other monomeric components are known in the art. Most of these polymeric materials have relatively high molecular weights and are disclosed as useful for various non-pharmaceutical products such as, for example, fibers, plastics and the like products. The preparation of homopolymers of itaconic anhydride having a broadly defined molecular weight range of 350 to 1,500,000 for use as builders in detergent formulations as disclosed in U.S. Pat. Nos. 3,308,067 and 3,560,529 illustrates another such non-pharmaceutical use.
In the pharmaceutical area, Drougas and Guile, J. Polymer Sci. 55, 297-302 (1961), describe the biological activity of copolymers of itaconic anhydride and styrene in relation to certain types of cancer. The disclosed molecular weights of these copolymers are in the range of 50,000 to 150,000. Hodnett et al., J. Med. Chem. 21 (7), 652-657 (1978), more recently describe the antitumor activity of poly(itaconic acid) against Sarcoma 180. The disclosed molecular weights from viscosity measurements of these polymers range from 44,000 to 250,000 (Table II).
Ammoniated derivatives of some of the foregoing and related types of polymeric materials are disclosed in general terms in various patents, for example, U.S. Pat. Nos. 2,313,565; 3,157,595; 3,840,499; and 3,998,907. Itaconic acid also is mentioned in long lists of monomeric materials in Canadian Pat. No. 664,326 for reaction with sundry olefinic components to provide copolymers which can then be ammoniated to form derivatives having antitumor activity. The disclosed molecular weights of these copolymers broadly range from 500 to 1,500,000.
Low molecular weight copolymers with amide-imide functionality and having antitumor properties are described in U.S. Pat. No. 4,255,537. The disclosed base copolymers are prepared by copolymerization of polycarboxylic anhydrides such as maleic anhydride with olefins such as ethylene and the like monomeric components. The base copolymer molecular weight ranges from about 300 to about 1500.